Sunday, May 25, 2014

If you know the tricks you can increase and decrease your caffeine tolerance by varying environmental factors. Ramp up the amount of exercise, broccoli and smoked meats ➲ maximize the clearance and minimize the effects of caffeine.

Actually I had hoped no-one would see the comment I made in the discussion revolving around a recent article about caffeine, but since a promise is a promise and I was stupid enough to promise that I would write an article on the genetic and environmental underpinnings of caffeine-over- and -under-metabolizers, I am sitting right here, digging up study after study, to find ... well, nothing conclusive.

According to analysis Welfare et al. conducted and published in June 1999, there is actually no significant polymorphism in CYP1A2 in Caucasians which could explain the interindividual variation in caffeine activity, we all know exists (Welfare. 1999) - meanwhile, scientists have identified a handful of polymorphism - albeit with partly unknown acute or chronic implications (see Table 1).

One year before, Schrenk et al. had already reported that smokers have significantly increased CYP1A2 activities. Compared to a non-smoker, a nicotine-junkie is thus much more prone to become "caffeine resistant", solely because he is metabolizing and excreting the drug much faster (Schrenk. 1998). Genetics and sex, on the other hand, appeared to make only a minor difference.

After Welfare's conclusion from 1999, it took another 3 years, before Rasmussen et al. published the results of an intriguing study in the peer-reviewed scientific journal Pharmacogenetics and Genomics. In said paper, Birgitte B. Rasmussen, Thomas H. Brix, Kirsten O. Kyvik and Kim Brøsen confirmed the observations Schrenk et al. had made and found, next to the caffeine ↔ nicotine and caffeine ↔ sex (male = high; female = low clearance) connections, another significant environmental effect: A highly significant reduction of caffeine clearance in women on oral contraceptives.

Did you know that the clearance of caffeine can vary to up to 40-fold within and between individuals (Kalow. 1991; Kashuba. 1998)? Or that Asian and African populations appear to metabolize caffeine at slower rate than Caucasians (Gunes. 2008)

No wonder, the scientists were after all also able to confirm that CYP1A2 does not only vary according to sex (higher activity in men vs. women = faster clearance in men vs. women), but is also induced by smoking and inhibited by oral contraceptives.

"In the subsequent analysis of heritability, we included
49 monozygotic twin pairs and 34 same gender dizygotic twin pairs
concordant for non-smoking and non-use of oral contraceptives.

Now that's a statistically significant correlation, but it does also show that even with identical genes, environmental (or epigenetic) influences are responsible for more than 20% of the effects of caffeine.

Upon closer scrutiny, Rasmussen et al. were even able to show that unique environmental effects seem to account for the remainder 0.275 (95% confidence interval, 0.178–0.423) of the inter-personal susceptibility to the effects of caffeine.

This does not change that the major determinant of CYP1A2 activity is still a genetic one, the fact that other studies, like Carmelli et al. (1990) report a heritability of only 36%, Kendler et al. (2007) who conducted one of the most recent investigations of the heritability of CYP1A2 activity say it's ~30-45% and rises from age 9–14 to remains stable, afterwards, I would not discard the possibility that your caffeine resistance or hyper-response is a result of certain dietary & lifestyle factors.

Now the question is: What are these environmental factors?

I don't pretend I could name them all, so I will just stick to those I can find within the hours I am willing to spend skimming study after study to abide by my promise:

meat, when it's cooked at high temperatures increases the clearance of caffeine (Sinha. 1994) - the exact extent is unknown and probably varies depending on the cooking method and overall consumption

broccoli and other brassica vegetables (similar effects have been reported for cumin and turmeric) increase the clearance of caffeine (Lampe. 2000) - in women the consumption of a high brassica diet (428g/day!) lead to 18% increase in CYP activity and thus caffeine clearance

exercise increases, specifically chronic exercise, increases the expression of CYP1A2 and thus the clearance of caffeine significantly - in a 1992 study by Vistisin by a whopping 70%! (Vistisen. 1992)

green tea extract increases the expression of CYP1A2 in the gut, already, consequently, your caffeine will be broken down before it even reaches the liver (Netsch. 2006) - interestingly enough, pure EGCG does not have this effect

gingko biloba increases CYP1A2 activity and caffeine clearance in the liver (Hellum. 2007) - specific data on the effect size is not available

insulin at least if you are diabetic insulin will reduce the half-life of caffeine by increasing - you guessed it - CYP1A2 activity (Flockhart. 2007)

proton pump inhibitors such as omeprazole have also been shown to induce CYP1A2 activity and should thus likewise lower the half-life of caffeine (Flockhart. 2007)

lutein has been shown to be associated with low CYP1A2 activity and could thus decrease caffeine clearance (Marchand. 1997)

dill, celery, parsley, parsnips and carrot coins decreases the clearance of caffeine (Lampe. 2000) - in women the consumption of high amounts of apiaceous veggies led to a -13% reduction in CYP activity and a correspondingly reduced clearance of caffeine

naringin from grapefruit reduces the clearance of caffeine (Fuhr. 1993) - the extent in the single serving study was -23% oral clearance of caffeine and +31% half- life

peppermint, chamomile, cannabis and dandelion teas are all relatively strong inhibitors of CYP1A2 activity and will thus increase the half-life and effects of caffeine

So, if you look at the first three inducers of caffeine clearance, I suppose you won't need an additional explanation why even non-pre-workout abusing physical culturists appear to be more or less resistant to the effects of caffeine, right? Right, ... meat + broccoli + exercise = massive increase in CYP1A2 activity and thus an increase in caffeine clearance that helps your liver to shuttle the CNS stimulant out of the system before it even gets to the central nervous system ;-)

Bottom line: Now that you know that you are doing to make caffeine less effectively, I would suggest you keep doing exactly that! Yes, you read me right! Exercise is good for you, and so are cruciferous vegetables. If you think you need a more pronounced boost from your morning coffee, work on improve your sleep schedule and / or reduce your training load (chances are you are overtraining and (ab-)using caffeine and other stims to make up for a lack of rest) - caffeine can replace adequate rest, once (see " Caffeine Works - Study Leaves No Doubt About It!" | read more), but not chronically. Don't fret! Look at the figure to the right-hand side!

That's actually a good thing: If the central nervous system didn't reduce it's own susceptibility to the stimulating effects of the world's favorite drug, coffee consumption would probably be associated with heart attacks and thus reductions, not increases in lifespan.

Yep! The findings of the Leisure World Cohort Study (Paganini-Hill. 2007), in which 8644 elderly women and 4980 elderly men were studied for 23 y, indicated that the daily consumption of up to 400 mg of caffeine significantly decreased (by 10%) the risk of dying from any cause (-10%).

And you know what? Studies like the one Mark Tarnopolsky and Cynthia Cupido published in volume 89 of the Journal of Applied Physiology in 2000 show: As long as you're not overtraining the physical ergogenic effects will remain intact, so that "caffeine potentiates low-frequency skeletal muscle force in habitual and nonhabitual caffeine consumers" (Tarnopolsky. 2000).

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